Follicular and sebaceous gland cell differentiation was investigated during treatment of acne patients with isotretinoin. Sebaceous glands were significantly reduced in volume and showed decreased metabolic activity as measured by glucose-6-phosphate dehydrogenase and succinic dehydrogenase enzyme activities. There was no measurable change in the volume of follicular duct epithelium or in its metabolic activity during treatment. Metabolic activity was also unchanged in the interfollicular epidermis, contrasting with the effects of another retinoid, etretinate. These findings provide no support for the proposition that alteration in the process of follicular keratinization forms a substantial part of the mode of action of isotretinoin.